Transcranial current stimulation (tCS) is a noninvasive brain stimulation technique in which weak, constant or slowly varying electrical currents are applied to the brain through the scalp. tCS includes a family of related noninvasive techniques including direct (tDCS), alternating (tACS) and random noise current stimulation (tRNS). These techniques use scalp electrodes with electrode current intensity to area ratios of about 0.3-5 A/m2 at low frequencies (typically <1 kHz) resulting in weak electric fields in the brain, with amplitudes of about 0.2-2V/m. The neuromodulatory effect of these fields
(Antal et al., 2008; Nitsche and Paulus, 2001, 2000; Terney et al., 2008) have been confirmed in many laboratories. In a typical tDCS experiment, a continuous current of 1-2 mA is applied for up to 20 min through two large stimulation electrodes (25-35 cm2). For therapeutic applications, such as post-stroke rehabilitation (Khedr et al. (2013)) or the treatment of depression (Loo et al. (2012)), tDCS is usually applied daily for five days, during one or more weeks.
While tCS interventions typically focus on a single cortical target, it is widely recognized today that many behavioral manifestations of neurological and psychiatric diseases are not solely the result of abnormality in one isolated brain region but represent alterations in brain networks (see, e.g., Fox et al. (2012c) and references therein). In this context, and provided a specification for the location and type of stimulation effects is available, brain networks become the target of neuromodulatory interventions. Advances in neuroimaging technology such as positron emission tomography (PET), electroencephalography (EEG), magnetoencephalography (MEG) and resting-state functional connectivity MRI (rs-fcMRI) are allowing us to non-invasively visualize brain networks in humans with unprecedented clarity. In a parallel and timely development, technologies have become available today which enable the use of more than two electrodes for stimulation (two is the minimum number for current stimulation), making possible true current-controlled multisite stimulation of brain networks. Determining the ideal configuration of a multi-electrode tCS system, however, is complicated by the fact that transcranial brain stimulation effects are largely non-local due to Ohmnic propagation effects. For this reason, optimization algorithms based on globally defined, cortical targeting data are needed.
As an especially interesting example, the use of rs-fcMRI seed maps is herein discussed (Shafi et al. (2012); Fox et al. (2012c)) for defining cortically extended tCS targets. In contrast to traditional task-based fMRI, resting state fcMRI examines correlations in spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal in the absence of any explicit input or output, while subjects simply rest in the scanner (see, e.g., Buckner et al. (2013) and references therein). A consistent observation is that regions with similar functional properties, such as the left and right motor cortices, exhibit coherent BOLD fluctuations even in the absence of movement under resting conditions. Negative correlations (anti-correlations) between regions with apparent opposing functional properties have also been observed (Fox et al. (2005)). Significant rs-fcMRI abnormalities have been identified across almost every major neurological and psychiatric disease (for a review see Fox and Greicius (2010)), and differences across subjects in rs-fcMRI are reproducible across scanning sessions and have been related to individual differences in anatomical connectivity and behavior.
One of the most valuable clinical uses of rs-fcMRI may be to predict how focal brain stimulation will propagate through networks, thus informing the ideal site for stimulation (Fox and Greicius (2010); Fox et al. (2012c)). Recently, Fox et al. (2012b) used rs-fcMRI to identify differences in functional connectivity between effective and less effective DLPFC stimulation sites (Fox et al. (2012c,a)). Significant differences in connectivity were seen with the subgenual cingulate (SG), a region repeatedly implicated in antidepressant response and an effective DBS target (Mayberg et al. (2005); Drevets et al. (2008); Mayberg (2009)). Based on this finding, Fox et al. used rsfcMRI with the SG to identify theoretically optimal TMS target coordinates in the left DLPFC (Fox et al. (2012b)). A similar strategy can be applied to other neurological diseases with effective or potentially effective DBS sites including Parkinson's disease, dystonia, essential tremor, Alzheimer's disease, and even minimally conscious state. An important challenge with this approach is that rs-fcMRI with an effective DBS site does not identify just a single cortical site, but many. In fact, it provides a continuous pattern across the cortical surface of regions that are both positively and negatively correlated with the deep brain stimulation site of interest. Realizing the full potential of this targeting approach thus requires the ability to simultaneously excite or inhibit multiple sites across the surface of the cortex. As will be seen below, the same occurs with targets from other imaging techniques, such as PET. While conventional TMS and tDCS technologies allow for only one or two stimulation sites, the multi-electrode approach perfectly complements this scientific and therapeutic need.
Next, some patent documents disclosing different proposals regarding the optimization of the configuration of multisite transcranial current stimulation are cited and briefly described.
U.S. Pat. No. 8,494,627 B2 discloses the automatic optimization of different parameters for multisite brain stimulation regarding an optimal stimulation pattern (such as voltage, current, activation time, location, sequence or number of electrodes), based on a forward model for the brain tissue obtained using finite element model and taking into account the brain response to different features, such as using a minimum number of electrodes, of current sources, giving a desired orientation of induced electric fields/current density, considering the electrical conductance as non-isotropic and or non-uniform, defining certain constraints such as maximum allowable currents of field intensities at various tissue locations.
Different optimization criteria are disclosed in U.S. Pat. No. 8,494,627 B2 formulated as a convex optimization problem and solved with a least one of linearly constrained Least Squares minimization, weighted Least Squares, Linearly Constrained Minimum Variance, maximum magnitude with a linear-norm constrains, or a convex optimization technique, although the scope of protection granted to said patent is limited to the optimizing of a first array of electrodes, the forming and posterior optimizing of a second array of electrodes from the first array of electrodes, by removing therefrom low current electrodes or electrodes with equal current and opposite polarity.
Although it could be deduced from some portions of the disclosure of U.S. Pat. No. 8,494,627 B2, that a cortical normal solution is sought, only concepts of electric fields radial and tangential to the skull to define a target are used and disclosed in detail therein.
U.S. Pat. No. 8,494,627 B2 discloses injecting current at several transcranial locations in a controlled fashion, i.e. a multisite stimulation, but neither a multitarget stimulation, i.e. the use of multisite stimulation to induce electric fields at cortical locations as determined by the choice of one or more well-delineated (isolated) target locations in the cortex with an associated weighting scheme, nor an extended cortical targeting and stimulation thereof, understood as the use of multisite stimulation to induce electric fields in the entire cortex as specified by a cortical target map together with an associated weight map, are disclosed in detail therein.
Chinese Patent Application Pub. No. CN102698360 also relates to the automatic optimization of stimulation parameters for tDCS, and, with that purpose, particularly discloses using a genetic algorithm taking into account current distribution and spatial distribution and weight coefficients, where the stimulation is a multichannel tDCS provided a plurality of channel electrodes of an electrode array, where each channel electrode has an independent control of the polarity and current strength delivered thereto.
CN102698360 does not either disclose a multitarget stimulation nor an extended cortical targeting, but only a multisite stimulation.
U.S. Patent Application Pub. No. US2013/0096363 describes methods, devices and systems for neuromodulation of deep brain targets using a combination of transcranial magnetic stimulation (TMS) and transcranial direct current (DC) stimulation, where the latter is used only to reduce or eliminate side-effects, such as seizures, when modulating one or more deep brain targets. In the specification of US2013/0096363 is stated that although tDCS has been used in conjunction with TMS, the two techniques have been applied only to cortical brain regions, and also that tDCS effectively only reaches the cortical surface of the brain, and not to elements of the brain which are not in contact with the subdural pool of cerebral spinal fluid, because the spread of electrical current depends upon this energy form passing through highly conductive media, thus not disclosing any indirect deep brain stimulation (DBS) to be provided with the tDCS.
US2013/0096363 does not describe either a multitarget stimulation nor an extended cortical targeting.